Mesenchymal stem cells for enhancing biological healing after meniscal injuries

Table 2 Summary of recent preclinical and clinical studies regarding tissue engineering using mesenchymal stem cells for meniscus healing

Ref.	Cell source	Preclinical/clinical	Model	Results
Walsh et al[163], 1999	BM-MSCs (type I collagen scaffold)	Preclinical	Rabbit	Meniscal defect was left untreated (group 1) or treated with periosteal autograft (group 2), a type I collagen sponge (group 3), or the sponge loaded with MSCs (group 4). In group 4, regenerated tissue was the most abundant. Grossly, transition zone was well healed. Regenerated meniscus established normal appearing tissue. At 24 wk, meniscus-like tissue was predominantly identified with proteoglycan staining on safranin O-fast green
Angele et al[18], 2008	BM-MSCs (composite scaffold composed of 70% completely derivatized hyaluronan-ester and 30% gelatin)	Preclinical	Rabbit	After 12 wk, pre-cultured implants integrated with the host tissue. 8 of 11 had meniscus-like fibrocartilage, compared with 2 of 11 in controls (P < 0.03). Cross-sectional width of the pre-cultured implant repair tissue was greater than controls (P < 0.004)
Zhang et al[166], 2009	BM-MSCs (transfection of human hIGF-1 gene combined with injectable calcium alginate gel)	Preclinical	Goat	At 16 wk, in treated group, meniscal defects were filled with regenerated tissue similar to normal meniscal fibrocartilage. Repair tissue was composed of cells embedded within fiber matrix. The proteoglycan content in treated group was higher than those in control groups
Zellner et al[164], 2010	BM-MSCs (sponge scaffold manufactured from 70% derivatized hyaluronan-ester and 30% gelatin)	Preclinical	Rabbit	At 12 wk, implantation of precultured chondrogenic MSC constructs showed fibrocartilage-like repair tissue with only partial integration with native meniscus. Non-precultured MSC group showed development of completely integrated meniscus-like tissue
Hong et al[164], 2011	BM-MSCs (matrix gel scaffold)	Preclinical	Rabbit	At 8 wk, no groups showed the healing response. There was no significant difference in the pathological criteria between treated and control groups
Moriguchi et al[167], 2013	S-MSCs [scaffold-free tissue engineered construct (TEC)]	Preclinical	Miniature pig	At 6 mo, MSC group showed tissue repair with fibro-cartilaginous tissue and good integration. The ratio of Safranin O positive area was significantly higher in treated group than in control group (P = 0.03). The treated group showed significantly reduced chondral lesions (P = 0.016) and better ICRS scores (P = 0.008)
Zellner et al[78], 2013	BM-MSCs (sponge scaffold manufactured from 70% completely derivatized hyaluronan-ester and 30% gelatin)	Preclinical	Rabbit	At 12 wk, the MSC groups showed fibrocartilage-like repair tissue, and better integration and biomechanical properties were identified especially in the precultured-MSC applied group
Katagiri et al[169], 2013	S-MSCs (aggregate of S-MSCs)	Preclinical	Rat	At 4 wk, the regenerated meniscus was larger and histological findings were closer to the normal meniscus in MSC-aggregate groups than in MSC-suspension group. The effects of MSC-aggregate were still observed at 12 wk. Luminescence intensity remained higher after 3 wk in the MSC-aggregate group
Desando et al[82], 2016	BM-MSCs and bone marrow concentrate (BMC) (hyaluronan-based biodegradable polymer)	Preclinical	Sheep	At 12 wk, BMC group showed a better repair ability in inhibiting OA progression than BM-MSC group. In addition, the BMC group showed the best results in meniscus regeneration
Qi et al[168], 2016	BM-MSCs (transplantation of MSCs sheet)	Preclinical	Rat	At 8 wk, histological analysis revealed that healed meniscus was similar to native tissue in the treated group. Furthermore, predominant collagen-rich matrix bridging the interface was identified and the regenerated meniscus integrated well with surrounding host meniscus
González-Fernández et al[100], 2016	BM-MSCs or A-MSCs (collagen repair patch)	Preclinical	Horse	At 1 yr, the control group had full-thickness defects. Defects remained in only 1 of the 6 menisci in MSC groups without any differences between A-MSC and BM-MSC groups. Histologically, quantity of regenerated meniscal tissue was better in MSC groups than in controls (P < 0.001)
Moradi et al[165], 2017	A-MSCs and articular chondrocyte (AC) (Polyvinyl alcohol/Chitosan (PVA/Ch) scaffold	Preclinical	Rabbit	At 7 mo, macroscopic and histologic studies revealed better results in AC/scaffold group followed by AC-A-MSC (co-culture)/scaffold and A-MSC/scaffold groups. Articular cartilages were best preserved in AC/scaffold group. Highest histologic scores were identified in the AC/scaffold group
Kondo et al[93], 2017	S-MSCs (aggregateof S-MSCs)	Preclinical	Monkey	The meniscus was larger and the modified Pauli’s histological score was better in treated group at 8 and 16 wk. At 16 wk, Mankin’s score for medial femoral condyle cartilage was better in treated group. T1rho values for regenerated meniscus was closer to the normal meniscus in treated group
Zellner et al[77], 2017	BM-MSCs (hyaluronan collagen composite matrix)	Preclinical	Rabbit	At 3 mo, MSC group showed meniscal defects completely filled with dense repair tissuea. Histologically, regenerated tissue was meniscus-like with typical pericellular meniscal cavities and extensive extracellular matrix. Immunostaining for type II collagen was moderately positive. The repaired tissue showed typically radially orientated collagen fibers. MSC group had significantly increased type II collagen gene expression and production (P < 0.05)
Whitehouse et al[96], 2017	BM-MSCs (collagen scaffolds)	Clinical	Human	Five patients were treated and there was significant clinical improvement in 3 patients. The 3 patients were asymptomatic at 24 mo without retear in MRI. Two required subsequent meniscectomies at 15 mo
Toratani et al[106], 2017	A-MSCs (high-density MSC scaffold-free allograft constructs (HDMACs))	Preclinical	Rabbit	Grossly, tissue healing was significantly greater in treated group at 2, 4, and 8 wk (P = 0.01). Safranin-O staining was positive at 2 wk and increased gradually over time in treated group. Histological scores were significantly higher in treated group at all weeks (P < 0.05)
Koch et al[102], 2018	BM-MSCs (polyurethane scaffolds)	Preclinical	Rabbit	At 12 wk, in both cell-free and MSC groups showed well-integrated and stable meniscus-like repair tissue. But, accelerated healing was notice in MSC group
Olivos-Meza et al[97], 2019	Peripheral blood MSCs (polyurethane scaffolds)	Clinical	Human	In tibial T2 mapping, values in MSC group increased slightly at 9 mo but returned to initial values at 12 mo. In control group, decrease from 3 mo to 12 mo was observed. This difference tended to be lower in control group compared with MSC group at 1 yr (P = 0.18). In the femur, a slight increase in MSC group compared with control group was observed (P > 0.05)

BM-MSCs: Bone marrow-derived mesenchymal stem cells; MSC: Mesenchymal stem cell; S-MSCs: Synovium-derived mesenchymal stem cells; ICRS: International Cartilage Repair Society; A-MSCs: Adipose-derived mesenchymal stem cells; OA: Osteoarthritis; MRI: Magnetic resonance imaging.